Abstract 1446: Induction of epithelial-to-mesenchymal transition (EMT) by SL-15 knockdown contributes to anoikis resistance in human colorectal cancer metastases

Abstract

Abstract Purpose of the study: Metastasis or systemic dissemination of cancer cells into secondary organs is responsible for 90% of cancer-related fatalities. Our team previously screened out SL-15 as therapeutic target of gastric cancer through the analysis of gene expression profiling. In this study, we investigated the roles of human SL-15 in colorectal cancer (CRC) metastasis. Experimental procedures: SL-15 levels of metastatic liver CRC tissues and of primary CRC tissues as well as of adjacent nontumour tissues were compared using quantitative RT-PCR. Transwell and wound healing methods were used to determine the migration/invasion abilities of CRC cells. Flow cytometery analysis was performed to measure the apoptotic ratio as well as the levels of E-cadherin/p53/SL-15. Confocal observation and Western blot analysis were used for studying the underlying mechanisms of small interfering RNA against SL-15 (siSL-15)-induced CRC metastasis. Results: The level of SL-15 was higher in the order of metastatic liver CRC tissues, primary CRC tissues and then the adjacent nontumor tissues. siSL-15 significantly induced the migration/invasion of CRC cells that was almost entirely suppressed by the co-expression of SL-15. Importantly, the application of siSL-15 contributes to anoikis resistance of CRC cells via the upregulation of zinc finger E-box-binding homeobox 1 (ZEB1) in stem-like subtype CRC cells and intestinal trefoil factor (ITF) in goblet- like subtype CRC cells by the inhibition of glycogen synthase kinase 3 β (GSK3β) and of β-catenin degradation, thereby leading to downregulation of E-cadherin as well as p53 degradation. Importantly, the interactions among SL-15/p53/GSK3β that were dissociated upon the application of siSL-15 were determined. Conclusions: SL-15 is more highly up-regulated in metastatic liver CRC cancer than in primary CRC cancer and the adjacent nontumor tissue: SL-15 knockdown contributes to anoikis resistance of CRC cells and CRC metastasis via inducing epithelial-to-mesenchymal transition as well as p53 degradation due to the dissociation of SL-15 with GSK3β and p53. Citation Format: Soo Young Jun, Hyun-Soo Cho, Jeong-Ju Lee, Jun-Ho Ahn, Ji-Yong Yoon, Jae-Hye Lee, Min Hyuk Choi, Nam-Soon Kim. Induction of epithelial-to-mesenchymal transition (EMT) by SL-15 knockdown contributes to anoikis resistance in human colorectal cancer metastases. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1446. doi:10.1158/1538-7445.AM2015-1446